While the development of an HIV vaccine that can induce neutralizing antibodies (nAbs) remains a top priority, nearly 3 decades of research in this arena has proven that this is a daunting task. However, recent results from the modestly protective RV144 vaccine trial argue that protection from infection can be achieved in the absence of nAbs and cytotoxic T cell responses, and this protection and may be linked to the induction of functional antibodies (Abs) that target specific epitopes on the viral V2 loop. Likewise, more than 3 decades of research have pointed to a role for non-neutralizing, innate immune-recruiting Abs in antiviral control and slower disease progression. Interestingly, over the last R01 funding period, it has become clear that in both the setting of vaccine-induced immunity and natural infection, the most functional antibody (Ab) responses are driven by HIV-specific IgG3 Abs. However, what these IgG3 antibodies target, how these IgG3 responses are induced, and most critically how they persist in some patients has yet to be defined. Here, we hypothesize that the rules of long-lived IgG3 selection can be learned from both vaccination and natural infection, with the hope that the induction of these potent humoral effector molecules prior to exposure to HIV may lead to durable protection from infection. Therefore, in this application, we propose to specifically dissect the specificity and functional profile of the HIV-specific IgG3 responses in both infection and vaccination. Based on these results, we will isolate antigen-specific IgG3 B cells to begin to learn the rules by which these B cells select a particular antibody subclass as well as how these responses may be artificially skewed towards IgG3 with adjuvants, T cell help, and/or cytokines. Together, these studies, linking antibody function to B cell programming will provide a first-in-class composite picture of the evolution of protective functional Abs and define the mechanisms by which protective immunity may be elicited through vaccination to gain enhanced control over the virus.